GDVII and other members of the GDVII subgroup of Theiler's murine encephalomyelitis viruses (TMEV) produce an acute, fatal neuronal disease in mice. In contrast, DA and other members of the TO subgroup of TMEV produce a chronic demyelinating disease with a persistent infection that has a restricted expression. TMEV provides an excellent experimental model for Multiple Sclerosis(MS). A better understanding of TMEV demyelination may clarify the pathogenesis of other demyelinating diseases, such as MS. We have two major thrusts in this proposal: First, we will delineate the genetic determinants for demyelination, virus persistence and restricted expression. We plan to carry this out by inoculating recombinant or mutated viruses prepared from: 1) intratypic DA- GDVII chimeric cDNAs, 2) chimeric cDNAs prepared between DA and DA non- demyelinating mutants, 3) DA cDNA with mutations in the L coding region. Second, we will determine the effect of DA genome and protein on the myelin-specific functions o oligodendrocytes by transfecting constructs with defective DA genomes. These latter studies may clarify how persistent TMEV disturbs oligodendrocyte function.